# Elucidating the Role of Binding Kinetics in the Development of Abl Kinase Drug Resistance

> **NIH NIH F30** · STATE UNIVERSITY NEW YORK STONY BROOK · 2021 · $38,248

## Abstract

PROJECT SUMMARY
The development of small molecule inhibitors has revolutionized targeted therapeutics, especially in the field of
protein kinases. However, pharmaceutical development continues to be plagued by two problems: (i) designing
specific drugs with limited off-target toxicity and (ii) combating the occurrence of resistance mutations in the
target of interest. The role of binding kinetics, referring to a ligand’s association and dissociation rate to its target,
are underexplored and underexploited in addressing these issues. In the non-equilibrium environment of the
human body, drug on- and off-rates have proven to be superior optimization parameters for candidate
compounds than the traditional IC50 and KD metrics. Furthermore, mutations that reduce drug residence time,
defined as how long a drug stays bound to its target, can presumably confer resistance to therapy.
Imatinib, the seminal achievement of rational drug design, inhibits the BCR-Abl oncoprotein and has reduced
the mortality rate for chronic myelogenous leukemia by 80%. Imatinib’s specificity for Abl kinase is due to its
conformational selectivity, and its success has sparked intense efforts to discover specific inhibitors of kinases
dysregulated in cancer and inflammatory disease. Despite its clinical success, relapse to imatinib therapy due to
resistance mutations is common, and a fundamental understanding of how mutations distant from the ligand
binding site cause resistance continues to elude us. We have preliminarily identified a series of patient-derived
resistance mutations that paradoxically show no change in equilibrium affinity for imatinib. We have also
validated that the Abl N368S mutant causes imatinib resistance by increasing drug dissociation rate. Therefore,
I propose using these Abl kinase mutations as a model system to explore how binding kinetics affect ligand
specificity, potency, and efficacy. My central hypothesis is that altered inhibitor binding or dissociation
kinetics could cause resistance independent of inhibitor affinity. I will explore this hypothesis by measuring
the effects of Abl kinase mutations on drug residence time and efficacy and by defining the conformational
changes of the Abl N368S substitution.
Through these studies, I will determine the structural mechanism of “kinetic resistance” mutations, a novel type
of drug resistance which I believe extends throughout the kinome. I will also elucidate key structural factors in
the conformational exchange of Abl kinase and the imatinib unbinding process. In addition, I will provide insight
into how prolonging in vivo drug action through slow dissociation rates can be applied to develop drugs with
minimal off-target toxicity. The contributions from this proposal are significant because they will validate altered
binding kinetics as both a novel mechanism of drug resistance in a highly-therapeutically relevant protein family
and as a viable strategy to improve drug specificity.

## Key facts

- **NIH application ID:** 10230830
- **Project number:** 1F30CA260771-01
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** Aziz Mohammedi Rangwala
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $38,248
- **Award type:** 1
- **Project period:** 2021-02-17 → 2025-02-16

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10230830

## Citation

> US National Institutes of Health, RePORTER application 10230830, Elucidating the Role of Binding Kinetics in the Development of Abl Kinase Drug Resistance (1F30CA260771-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10230830. Licensed CC0.

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